Our long-term goal is to develop means of improving the quality of epidural opioid analgesia for patients in pain following surgery, trauma or cancer and its treatment. This research is designed to identify molecular characteristics that determine the balance between diffusion of opioids and other drugs across the meninges and drug uptake by the epidural venous plexus. The specific aims of this consortium project are to 1) determine which meningeal tissue - dura, arachnoid, or pia mater - is the principal barrier to diffusion of opioids, 2) identify physicochemical factors that influence meningeal permeability of drugs, 3) apply physicochemical information to prediction of meningeal permeability of opioids and alpha2-adrenergic agonists, 4) develop methods for modifying epidural analgesic availability to promote their meningeal diffusion, 5) determine the route (cisternal/venous) and kinetics of redistribution of epidurally administered drugs to systemic and supraspinal sites as a function of: molecular weight, lipid partition coefficients and solubility modifying agents, and 6) correlate the time course of redistribution of drug from the epidural space with the effects on spinal (analgesia) and supraspinally mediated responses (ventilatory response to C02 elevation). To address these issues, we will conduct two series of experiments in parallel at FHCRC and UCSD: 1) in vitro diffusion studies using freshly harvested meningeal tissue to determine the feasibility of predicting meningeal permeability from physicochemical properties of analgesic drugs and in vivo studies using a chronically catheterized epidural dog model to identify the routes and extent of redistribution of epidural opioids by monitoring drug concentration over time in lumbar and cisternal cerebrospinal fluid and systemic circulation. Both components of this project will also evaluate the utility of using physical and chemical means to control the rate of release of opioids in the epidural space for improving the spinal selectivity of drug action. These studies will permit us to define the characteristics of spinally administered agents which should be sought in the further development of this important clinical tool to minimize side effects and optimize the therapeutic advantages.